Hypoxia-mediated m⁶A modulation in hepatocellular carcinoma: a comprehensive review

Area of Science:

• Oncology
• Epigenetics
• Molecular Biology

Background:

• Hepatocellular carcinoma (HCC) is a leading cause of cancer death with poor prognosis, especially in cirrhotic patients.
• The hypoxic tumor microenvironment in HCC correlates with poor response to targeted and immunotherapies.
• N6-methyladenine (m6A) epigenetic modification is linked to tumor immune evasion, metabolic reprogramming, and ferroptosis resistance.

Purpose of the Study:

• To elucidate the molecular mechanisms of the hypoxia-m6A axis in HCC progression.
• To explore the clinical potential of the hypoxia-m6A axis as a biomarker and therapeutic target for HCC.
• To discuss current limitations and future research directions for targeting this axis in HCC.

Main Methods:

• Systematic review of molecular mechanisms involving hypoxia-inducible factor (HIF-1α) and m6A-modifying enzymes (METTL3, FTO, YTHDF2).
• Analysis of the interplay between hypoxia and m6A modification in HCC.
• Clinical perspective on the hypoxia-m6A axis as a therapeutic target.

Main Results:

• Hypoxia-inducible factor (HIF-1α) and key m6A enzymes (METTL3, FTO, YTHDF2) jointly regulate HCC progression in a hypoxic microenvironment.
• The hypoxia-m6A axis plays a crucial role in tumor immune evasion, metabolic reprogramming, and ferroptosis resistance in HCC.
• Evidence suggests the hypoxia-m6A axis is a promising biomarker and therapeutic target for overcoming treatment resistance in HCC.

Conclusions:

• The hypoxia-m6A axis presents novel therapeutic perspectives for managing HCC.
• Targeting this axis could overcome treatment resistance in advanced HCC.
• Future research should focus on advanced nanomedicines, immune checkpoint inhibitors, and multimodal imaging for personalized HCC treatment.